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Understanding the role of gut bacteria and disease

The human body contains a mind-boggling 10 times more bacteria than it does human cells. For most people, the immune system protects against this army of bacterial invaders without leading to constant inflammation. Understanding how that process works — and when it doesn’t — could be the key to new treatments for inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

That’s the focus of Nita Salzman, MD, PhD, a pediatric gastroenterology researcher who co-leads the Immunology, Inflammation and Infection unit for Children’s Hospital of Wisconsin Research Institute. Dr. Salzman has spent 15 years studying antimicrobial peptides produced by Paneth cells in the small intestine, which play an important role in the immune system. Then, other researchers discovered that many patients with Crohn’s disease have abnormal Paneth cells. Suddenly, Dr. Salzman’s years of basic science research had critically important implications for translational research involving patients with inflammatory bowel diseases. It underscores the importance of basic research, she says.

“For years and years we were studying Paneth cells and antimicrobial peptides, with people saying, ‘These aren’t important. Why are these important?’ and it can be difficult to get grant funding,” she says. “But its relevance explodes on the scene unexpectedly. … It’s hard to guess what’s going to be important, what’s going to be related to a certain disease.”

Dr. Salzman’s research has shown that Paneth cells that produce the wrong amount or types of antimicrobials lead to the wrong type of bacteria growing at the mucosal surface, which may then help trigger the immune system to go into overdrive. The inflammation can led to the pain, cramping and chronic diarrhea associated with inflammatory bowel diseases.

“A current prevailing theory in Crohn’s disease is that genetically susceptible individuals are having an immune response to their own colonizing bacteria, which is why those patients are inflamed all the time,” Dr. Salzman says.

Now, in a clinical study funded by the Crohn’s and Colitis Foundation of America (CCFA), Dr. Salzman’s lab is studying microbial colonization in more than 300 children: some who have Crohn’s disease or ulcerative colitis, and those who do not but who need colonoscopies for other reasons. Researchers analyze small intestine tissue collected during colonoscopies and stool samples, as well as blood work to examine genes associated with Crohn’s disease. The goal is to learn whether there’s an association between abnormalities in Paneth cell function, bacterial composition and bacterial behavior at the mucosal surface, Salzman says.

Current treatments for Crohn’s are effective but also impair the immune system, leaving patients at risk for infection. But if bacteria in the gut contribute to inflammation, then doctors might be able to help patients by simply changing their bacterial composition through diet or probiotics.

“If we could either develop appropriate diets to enhance the growth of certain bacteria, or have people ingest certain bacteria or bacterial byproducts to prevent or dampen inflammation from the point of inside of the gut, you might be able to free people from having to take these more serious drugs,” Dr. Salzman explains.

Dr. Salzman’s lab plans to participate in the next phase of the CCFA-sponsored study, which will focus on identifying possible ways to intervene in the disease process based on what they’ve learned about the role of intestinal bacteria.

“I think it’s likely that Crohn’s disease is the result of many causes, that everybody gets to this chronic inflammation in a somewhat different way, and so one treatment may not fit all,” she says. “It’s possible that maybe by evaluating an individual’s genetics and their microbial colonization and their gene expression, we might be able to tailor treatment.”